NMNAT1 Mutations Linked To Leber Congenital Amaurosis, Study Says

July 30, 2012

A five-country international team, led by Casey Eye Institute Molecular Diagnostic laboratory, BGI and Zhejiang University School of Medicine First Affiliated Hospital identified the NMNAT1 mutations as a cause of Leber congenital amaurosis (LCA), one of the most common causes of inherited blindness in children. The latest study was published online in Nature Genetics, reporting the genetic characteristics underlying some LCA patients, and providing important evidences that support NMNAT1 as a promising target for the gene therapy of LCA.

LCA is an inherited retinal degenerative disease characterized by severe loss of vision at birth. It is estimated that LCA occurs in 2 to 3 per 100,000 newborns. Currently a lot of studies are being done on LCA. Scientists found that LCA could result from mutations in at least 17 genes, all of which are necessary for normal vision and play important roles in the development and function of the retina. More importantly, gene replacement therapy has been successful in animal models and in humans more studies are underway. However, the genetic characters for about 20-30% LCA patients are still unknown.

In this study, the researchers sequenced the whole exome of an LCA patient with no previously identified mutations. They identified 2,460 previously unreported variants. Through a series of screening and analysis, the result indicated that the gene NMNAT1 may serve as a candidate for LCA. Previous studies have shown that NMNAT1 plays an important role in axonal degeneration, because it could encode an enzyme in the NAD (Nicotinamide adenine dinucleotide) biosynthesis pathway associated with protection against axonal degeneration.

In the further evaluation of NMNAT1, the researchers used Sanger sequencing to analyze 50 unrelated LCA patients with no previously identified mutations, and they found that ten patients carried NMNAT1 mutations. By relating the clinical phenotypes of LCA patients with the mutations, the researchers found that the severity of LCA may correlate with the types of NMNAT 1 mutation: the patients carrying both of the missense variant (c.769G>A, p.Glu257Lys) and nonsense variant (c.507G>A, p.Trp169*) were all blind at birth; while those who carrying only missense variant (c.769G>A, p.Glu257Lys) may develop poor vision within a few years after birth.

Professor Ming Qi, Chief Scientist at BGI, Director of Center for Genetic and Genomic Medicine, Zhejiang University School of Medicine First Affiliated Hospital and James D. Watson Institute of Genome Sciences, said, “LCA is one of the most common causes of inherited blindness in childhood. The study on NMNAT1 lays a solid foundation for understanding genetic characteristics of LCA and other related congenital blindness diseases. It is also an important step forward for developing new molecular diagnosis and gene therapy.”